Notable Trends and Companies to Follow in Neuroscience
Historically, the approval rate for medicines treating central nervous system (CNS) disorders was low. By 2022, the success rate for CNS assets from phase 1 through to regulatory submission was only 5–6%.
The failure of pharmaceutical companies to bring CNS medications to the market can be attributed to factors such as a limited understanding of disease mechanisms and challenges in delivering drugs across the blood-brain barrier. Nevertheless, recent technological advancements and an improved understanding of disease pathophysiology led to expanding the CNS pipeline.
A recent report shows that the CNS pipeline has grown by 31%, constituting 14% of the overall industry R&D pipeline. Moreover, the approval of the first drug for spinal muscular atrophy (SMA) developed by Ionis Pharma and Biogen was a significant stride that revitalized interest in the field and demonstrated the ability of innovative treatments to address complex neurological disorders.
Hot Deals of 2023 Involving Modulators of Muscarinic Receptors
In December 2023, Bristol Myers Squibb expanded its neuroscience portfolio by acquiring Karuna Therapeutics for $14.0 billion. Karuna’s leading candidate, KarXT (xanomeline-trospium), has a dual action on M1 and M4 muscarinic receptors without affecting the dopaminergic pathway.
KarXT is efficient in patients with schizophrenia as it reduces both positive and negative symptoms of the condition, which affects about 24 million people worldwide. When the FDA approves KarXT, it will become the first novel treatment for schizophrenia in decades.
The same month, AbbVie boosted its neurological and psychiatric disorder pipeline by purchasing Cerevel Therapeutics for $8.7 billion. This move will advance AbbVie's capabilities in addressing Alzheimer's, Parkinson's, psychosis, epilepsy, and panic disorders.
Cerevel's promising drug, emraclidine, is in the Phase 2 trial for schizophrenia. Emraclidine acts on M4 receptors, and similar to KarXT, it doesn’t directly affect dopamine D2 receptors, which hypothetically will prevent adverse effects that are common for available antipsychotic drugs.
Muscarinic receptors are part of the cholinergic pathway in the brain. Therefore, drugs targeting this pathway affect brain chemistry differently from currently available medicines that act on receptors of dopamine or serotonin, the two other well-known neuromediators. Because dopamine is essential for multiple functions in the brain, e.g., motor control, dampening D2 receptors leads to adverse effects.
The market for schizophrenia treatments targeting muscarinic receptors alone is estimated at $10 billion. With the acquisition mentioned, AbbVie and BMS strive to take leading positions in the market for muscarinic receptor drugs. Other companies in this space include Neurocrine Biosciences, Sosei Heptares, Neumora Therapeutics, MapLight Therapeutics, and Anavex Life Science.
Companies Bringing Innovations to Improve the Psychiatric and Mental Health
In September 2023, Otsuka acquired Mindset Pharma for $59.1 million to accelerate the development of the new generation of serotonin 5-HT2A receptor agonists to treat treatment-resistant depression and post-traumatic stress disorder (PTSD).
Another acquisition of a brain chemistry modifying asset was accomplished by AbbVie in 2022 when the pharma giant purchased Syndesi. ABBV-552 is a small molecule that acts upon targeting synaptic vesicle glycoprotein 2A (SV2A), which enhances synaptic transmission. It’s currently in Phase 2 clinical trials for Alzheimer’s disease (AD), with the potential to improve cognitive impairments and other symptoms concurrent with AD.
Alto Neuroscience, which recently went public, focuses on applying machine learning to identify brain-based biomarkers based on EEG data. Its most advanced programs are being evaluated in ongoing Phase 2b trials in major depressive disorder (MDD).
Known Since Aztechs, Psychedelics are in Clinical Trials Today
Algernon Pharmaceuticals is developing a psychedelic that can be naturally synthesized in the human brain to treat traumatic brain injury (TBI) and stroke. The compound DMT is believed to promote neuritogenesis and neuroplasticity by upregulating the expression of brain-derived neurotrophic factor (BDNF). Phase 1 is currently underway in the Netherlands.
Psilocybin has been known since ancient times and is used for spiritual and religious purposes. Today, it is recognized as a potential medicinal agent for treatment-resistant major depressive disorder. PurMinds™ is developing botanical psilocybin, hoping to bring positive changes in the lives of patients for whom standard antidepressants failed to improve their conditions.
Major Developments in the Areas of Neurological Indications
In the neuroscience market, the mental health pipeline accounts for only 20%, whereas the rest is attributed to neurological disorders. The incidence of some devastating neurological conditions is high. For example, every year, around 5 million people are diagnosed with Alzheimer's disease (AD). AD affects memory and cognitive functions, depersonalizes, and brings enormous emotional and financial burdens to the families of patients.
The FDA approves Biogen’s Second Antibody to Treat Alzheimer’s.
Leqembi is a monoclonal antibody developed by Elisay and Biogen that became the first therapy that proved to clear beta-amyloid plaques and simultaneously slow down the progression of cognitive decline in AD patients.
The antibody received its full FDA approval in the summer of 2023, finally proving the amyloid hypothesis, which has not successfully produced drugs that slow disease progression and cognitive decline over 16 years of research. Alongside approval in China, Lequembi is generating $1.5 million in weekly sales.
Additionally, Biogen expanded its Central Nervous System (CNS) portfolio by acquiring Reata Pharmaceuticals in August 2023 for $7.3 billion, gaining access to Skyclarys, the only approved drug for Friedreich's Ataxia. Furthermore, Biogen entered into a $51 million collaboration with Alcyone Therapeutics to develop the ThecaFlex DRx™ System, an implantable device for the routine subcutaneous administration of antisense oligonucleotide (ASO) therapies to the cerebrospinal fluid. This development aims to support the marketing of Spinraza and other ASO therapies.
Small Biotech Companies Drive Innovations in the Market of CNS Medicines
Small biotech companies’ unique science is often a source of innovations. For example, Caraway Therapeutics is researching cellular waste disposal mechanisms. Caraway's leading projects focus on the TRPML1 ion channel, crucial for removing lysosomal waste. The company is investigating the potential of targeting this protein to address Parkinson’s disease associated with GBA gene mutations, alongside other rare diseases outside the central nervous system. Recently, Merck has acquired Caraway Therapeutics for $610 million. This acquisition follows Merck's prior investment in the TRPML1 pathway, demonstrated by its 2019 purchase of Calporta Therapeutics for $576 million, a small biotech specializing in TRPML1-targeting compounds.
NRG Therapeutics focuses on mitochondrial dysfunction to create therapeutics that can slow the progression of neurodegenerative disorders like PD and Amyotrophic Lateral Sclerosis (ALS, also called motor neuron disease). Now, the company is working on the preclinical development of small molecule assets that target and inhibit the mitochondrial permeability transition pore (mPTP) via a new mechanism of action.
Companies Focusing on Preventing Neuroinflammation
Muna Therapeutics is a company that focuses on preventing neuroinflammation to protect adequate brain functions and prevent memory loss. Muna’s drug discovery platform focuses on discovering and validating small molecules that target microglia, the most prominent immune cells of the CNS.
Muna’s two drug discovery programs approach the opposite roles of microglia in CNS pathologies. The first and most advanced program is a TREM2 agonist to boost brain clearance. TREM2 is expressed in microglia cells, and variation of this gene is associated with a higher risk of developing neurodegenerative diseases. The second program is a blocker of a Kv1.3, a potassium channel expressed in microglia, that is involved in inflammatory mechanisms of action of microglia that often lead to neural damage.
Immunic, another company targeting neuroinflammation, has a drug in Phase 3 clinical study to improve the lives of patients with multiple sclerosis (MS). Their lead drug, vidofludimus calcium, activates the neuroprotective transcription factor Nurr1 with direct neuroprotective properties.
The compound is also known as an inhibitor of the dihydroorotate dehydrogenase (DHODH), which keeps T-cells and B-cells overactive. Vidofludimus calcium is also efficient in relapsing-remitting MS; it reduces lesions and serum neurofilament light chain levels, or NfL, a biomarker for axonal damage.
Arialys emerged in 2021 and was named one of the most innovative start-ups in 2023. The company focuses on the treatment of NDMA receptor encephalitis (ANRE), an autoimmune condition that prevents the transmission of glutamate and causes seizures and psychosis. ART5803, a single-arm antibody, rescues ANRE by binding and hiding an epitope of NDMA receptor from auto-reactive antibodies. The asset was acquired from Astellas Pharma in 2022. In 2023, Arialys raised $58 million to continue the development of ART5803.
Schrodinger, an AI-powered drug discovery leader, also addressed neuroinflammation by targeting LRRK2, a potential target for treating PD. Variants of LRRK2 might drive microglia to acquire pro-inflammatory functions, exacerbating neurodegeneration. Schrodinger successfully generated the cryo-microscopy structure of the LRRK2 after acquiring XTAL BioStructures, which specializes in X-ray crystallography for protein mapping. Generation of the 3D model allows Schrodinger to discover efficient inhibitors of LRRK2. Furthermore, the company has entered a multi-part agreement with Otsuka Pharmaceutical and its subsidiary Astex Pharmaceuticals, including discovery initiatives aimed at an emerging Central Nervous System (CNS) disease target.
Companies Combating Neural Nyperexcitability
QurAlis is a clinical-stage company that addresses amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neurodegenerative diseases. Their selective Kv7.2/7.3 ion channel opener is in a Phase 1 clinical study for treating hyperexcitability-induced disease progression in ALS.
Previously, a drug targeting this channel demonstrated promising results in patients with epilepsy, but its marketing was terminated due to side effects. Quaralis's QRL-101 can decrease motor neuron hyperexcitability-induced excitotoxicity, preventing ALS's progression.
Companies Leveraging RNA and Gene Therapies to Target CNS
Novartis has acquired DTx Pharma for an upfront payment of $500 million, securing the FALCON platform to enhance its neuroscience endeavors. This investment allows Novartis to develop therapies for unmet medical needs, including a preclinical therapy for Charcot-Marie-Tooth disease type 1A (CMT1A), a neuromuscular disorder with no approved treatments.
The acquisition also encompasses two additional preclinical programs addressing neuromuscular and central nervous system disorders. Through this acquisition, valued at potentially $1 billion with milestone payments, Novartis aims to bolster its RNA-based therapeutic capabilities, focusing on advancing treatments for conditions like CMT1A.
AviadoBio, specializing in CNS gene therapy, is focused on developing innovative treatments to slow or halt neurodegenerative diseases by targeting their genetic causes. The company's platforms include gene-supplement and gene-silencing technologies, along with advanced surgical delivery methods to enhance treatment distribution.
AviadoBio's portfolio features therapies and devices to treat frontotemporal dementia (FTD) and ALS. FTD is early-onset dementia that affects personality and behavior. AVB-101 is AviadoBio’s lead candidate for FTD linked to mutations in the progranulin (GRN) gene (FTD-GRN).
This therapy involves a one-time infusion of the GRN gene directly into the thalamus, aiming to restore GRN protein production and distribution across the brain, potentially stopping FTD progression.
Topic: Next-Gen Tools
